Method for preventing or inhibiting loss of cognitive function employing a combination of an ace inhibitor and a drug that acts at serotonin receptors

ABSTRACT

A method is provided for imhibiting loss of cognitive functon, including memory, which may or may not be associated with Alzheimer&#39;s disease, by administering an ACE inhibitor, such as captopril, fosinopril, zofenopril or ceranapril in combination with a drug that acts as serotonin receptors such as zacopride, over a prolonged period of treatment.

FIELD OF THE INVENTION

The present invention relates to a method for inhibiting loss ofcognitive function, including memory, which may or may not be associatedwith Alzheimer's disease, employing an ACE inhibitor, such as captopril,SQ 29,852, zofenopril, fosinopril or enalapril, in combination with adrug that interacts with serotonin receptors in the brain, such aszacopride.

BACKGROUND OF THE INVENTION

Angiotensin converting enzyme inhibitors (ACEi) and 5-HT₃(5-hydroxytryptamine₃) receptor antagonists have previously been shownto improve the basal performance of laboratory animals in habituationparadigms and also to overcome the impairment induced by scopolamine(Costall et al (1989), "The effects of ACE inhibitors captopril andSQ29,852 in rodent tests of cognition." Pharmacol. Biochem. Behav. 33;573-579; Barnes, J. M., et aI (1990), "The effects of ondansetron, 5-HT₃receptor antagonist, on cognition in rodents and primates." Pharmacol.Biochem. Behav. (35; 955-961).

U.S. Pat. Nos. 4,046,889 and 4,105,776 to Ondetti et al disclosesproline derivatives, including captopril, which are angiotensinconverting enzyme (ACE) inhibitors useful for treating hypertension.

U.S. Pat. No. 4,337,201 to Petrillo discloses phosphinylalkanoylsubstituted prolines, including fosinopril, which are ACE inhibitorsuseful for treating hypertension.

U.S. Pat. No. 4,374,829 discloses carboxyalkyl dipeptide derivatives,including enalapril, which are ACE inhibitors useful for treatinghypertension.

U.S. Pat. No. 4,452,790 to Karanewsky et al, discloses phosphonatesubstituted amino or imino acids and salts thereof and covers(S)-1-[6-amino-2-[[hydroxy(4-phenylbutyl)-phosphinyl]oxy]-1-oxohexyl]-L-proline(ceranapril, SQ 29,852). These compounds are ACE inhibitors useful intreating hypertension.

U.S. Pat. No. 4,316,960 to Ondetti et al, discloses ether and thioethermercaptoacyl prolines which are ACE inhibitors useful in treatinghypertension. This Ondetti et al patent covers zofenopril.

U.S. Pat. No. 4,931,430 to Sudilovsky et al, discloses a method forpreventing or treating anxiety employing an ACE inhibitor in combinationwith a calcium channel blocker.

DESCRIPTION OF THE INVENTION

In accordance with the present invention, a method is provided forinhibiting loss of cognitive functions such as memory, attention span,concentration and ability to learn or for treating or delayingprogression of Alzheimer's disease or other types of dementias and/ormemory disorders, including age-associated memory impairment (all ofwhich are included under the term cognitive function), in mammalianspecies, over a prolonged period, wherein a therapeutically effectiveamount of an angiotensin converting enzyme inhibitor and a drug thatinteracts with serotonin receptors in the brain, is systemically, suchas orally or parenterally, administered over a prolonged period, toinhibit loss of cognitive function during such period.

"Drugs that interact with serotonin receptors in the brain" and as suchare employed in the method of the invention will hereinafter be referredto as "drugs that act at serotonin receptors." These drugs may or maynot be 5-HT₃ antagonists.

The method of the invention is useful in treating or delayingprogression of primary degenerative dementias arising in the senium andpresenium such as Alzheimer's disease, Pick's disease and Binswanger'sdisease, and vascular dementias such as arteriosclerotic dementiasincluding multiple infarct dementia and Binswanger's disease.

With respect to the combination of ACE inhibitor and a drug that acts atserotonin receptors in accordance with the present invention, the ACEinhibitor will be employed in a weight ratio to the drug that acts atserotonin receptors of within the range of from about 0.0005:1 to about1×10⁷ :1 and preferably from about 0.002:1 to about 25×10⁴ :1.

The angiotensin converting enzyme inhibitor which may be employed hereinincludes substituted proline derivatives, such as any of those disclosedin U.S. Pat. Nos. 4,046,889 or 4,105,776 to Ondetti et al mentionedabove, with captopril, that is,1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline, being preferred,carboxyalkyl dipeptide derivatives, such as any of those disclosed inU.S. Pat. No. 4,374,829 mentioned above, withN-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline, that is,enalapril, being preferred.

Other examples of angiotensin converting enzyme inhibitors suitable foruse herein include any of the phosphonate substituted amino or iminoacids or salts disclosed in U.S. Pat. No. 4,452,790 with(S)-1-[6-amino-2-[hydroxy-(4-phenylbutyl)phosphinyl]oxy]-1-oxohexyl]-L-proline(ceranapril, SQ 29,852) being preferred, phosphinylalkanoyl prolinesdisclosed in U.S. Pat. No. 4,168,267 mentioned above with fosinoprilbeing preferred, mercaptoacyl derivatives of substituted prolines,disclosed in U.S. Pat. No. 4,316,906 with zofenopril being preferred,any of the phosphinylalkanoyl substituted prolines disclosed in U.S.Pat. No. 4,337,201 discussed above, and the phosphonamidates disclosedin U.S. Pat. No. 4,432,971 discussed above.

Other examples of ACE inhibitors that may be employed herein includeBeecham's BRL 36,378 as disclosed in European patent Nos. 80822 and60668; Chugai's MC-838 disclosed in CA. 102:72588v and Jap. J.Pharmacol. 40:373 (1986); Ciba-Geigy's CGS 14824(3-([1-ethoxycarbonyl-3-phenyl-(1S)-propyl]-amino)-2,3,4,5-tetrahydro-2-oxo-1-(3S)-benzazepine-1acetic acid HCl) disclosed in U.K. Patent No. 2103614 and CGS 16,617(3(S)-[[(1S)-5-amino-1-carboxypentyl]-amino]-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-ethanoicacid) disclosed in U.S. Pat. No. 4,473,575; cetapril (alacepril,Dainippon) disclosed in Eur. Therap Res 39 671 (1986); 40:543 (1986);ramipril (Hoechst) disclosed in Eur. Patent No. 79-022 and Curr. Ther.Res 40:74 (1986); Ru 44570 (Hoechst) disclosed in Arzneimittelforschung35:1254 (1985), cilazapril (Hoffman-LaRoche) disclosed in J. Cardiovasc.Pharmacol 9:39 (1987); Ro 31-2201 (Hoffman-LaRoche) disclosed in FEBSLett. 165:201 (1984); lisinopril (Merck) disclosed in Curr. Therap. Res.37:342 (1985) and Eur. patent appl No. 12-401, indalapril (delapril)disclosed in U.S. Pat. No. 4,385,051; rentiapril (fentiapril, Santen)disclosed in Clin. Exp. Pharmacol. Physiol. 10:131 (1983); indolapril(Schering) disclosed in J. Cardiovasc. Pharmacol. 5:643, 655 (1983);spirapril (Schering) disclosed in Acta. Pharmacol. Toxicol. 59 (Supp. 5):173 (1986); perindopril (Servier) disclosed in Eur. J. Clin.Pharmacol. 31:519 (1987); quinapril (Warner-Lambert) disclosed in U.S.Pat. No. 4,344,949 and CI 925 (Warner-Lambert)([3S-[2[R(*)R(*)]]3R(*)]-2-[2-[[1-(ethoxy-carbonyl)-3-phenylpropyl]amino[-1-oxopropyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylicacid HCl) disclosed in Pharmacologist 26:243, 266 (1984), WY-44221(Wyeth) disclosed in J. Med. Chem. 26:394 (1983).

Preferred are those ACE inhibitors which are proline or substitutedproline derivatives, especially ceranapril.

The above-mentioned U.S. patents are incorporated herein by reference.

The drug that acts at serotonin receptors suitable for use herein may bezacopride (benzamide zacopride), 3αa-tropanyl-1H-indole-3-carboxylicacid ester (ICS 205930, Sandoz);[endo]N-(9-methyl-9-azabicyclo-[3,3,1]-non-3-yl)-1-methyl-1H-indazole-3-carboxamidehydrochloride (BRL 43694, Granisetron, Beecham);(1αH,3α,5αH-tropan-3-yl-3,5-dichlorobenzoate (MDL 72222, Merrell Dow);ondansetron; buspirone; and ritanserin.

A preferred combination in accordance with the present invention isceranapril and zacopride.

In carrying out the method of the present invention, the angiotensinconverting enzyme inhibitor in combination with the drug that acts atserotonin receptors may be administered to mammalian species, such asmonkeys, dogs, cats, rats and humans, and as such may be incorporated ina conventional systemic dosage form, such as a tablet, capsule, elixiror injectable. The above dosage forms will also include the necessarycarrier material, excipient, lubricant, buffer, antibacterial, bulkingagent (such as mannitol), anti-oxidants (ascorbic acid or sodiumbisulfite) or the like. Oral dosage forms are preferred, althoughparenteral forms such as intramuscular, intraperitoneal, or intravenousare quite satisfactory as well.

The dose administered must be carefully adjusted according to age,weight and condition of the patient, as well as the route ofadministration, dosage form and regimen and the desired result

Thus, for oral administration, a satisfactory result may be obtainedemploying the ACE inhibitor in an amount within the range of from about0.005 mg/kg to about 100 mg/kg and preferably from about 0.01 mg/kg toabout 25 mg/kg, in combination with the drug that acts at serotoninreceptors in an amount within the range of from about 0.010 μg/kg toabout 10 mg/kg and preferably from about 0.1 μg/kg to about 5 mg/kg,with the ACE inhibitor and drug that acts at serotonin receptors beingemployed together in the same oral dosage form or in separate oraldosage forms taken at the same time.

A preferred oral dosage form , such as tablets or capsules, will containthe ACE inhibitor in an amount of from about 0.1 to about 500 mg,preferably from about 5 to about 200 mg, and more preferably from about25 to about 150 mg, with the drug that acts at serotonin receptors in anamount of from about 1 μg to about 200 mg, preferably from about 5 μg toabout 150 mg, and more preferably from about 10 μg to about 100 mg.

For parenteral administration, the ACE inhibitor will be employed in anamount within the range of from about 0.005 mg/kg to about 10 mg/kg andpreferably from about 0.01 mg/kg to about 1 mg/kg, and the drug thatacts at serotonin receptors will be employed in an amount within therange of from about 0.005 μg/kg to about 20 mg/kg and preferably fromabout 0.01 μg/kg to about 10 mg/kg.

The composition described above may be administered in the dosage formsas described above in single or divided doses of one to four timesdaily. It may be advisable to start a patient on a low dose combinationand work up gradually to a high dose combination.

Tablets of various sizes can be prepared, e.g., of about 50 to 700 mg intotal weight, containing one or both of the active substances in theranges described above, with the remainder being a physiologicallyacceptable carrier of other materials according to acceptedpharmaceutical practice. These tablets can, of course, be scored toprovide for fractional doses. Gelatin capsules can be similarlyformulated.

Liquid formulations can also be prepared by dissolving or suspending oneor the combination of active substances in a conventional liquid vehicleacceptable for pharmaceutical administration so as to provide thedesired dosage in one to four teaspoonfuls.

Such dosage forms can be administered to the patient on a regimen of oneto four doses per day.

According to another modification, in order to more finely regulate thedosage schedule, the active substances may be administered separately inindividual dosage units at the same time or carefully coordinated times.Since blood levels are built up and maintained by a regulated scheduleof administration, the same result is achieved by the simultaneouspresence of the two substances. The respective substances can beindividually formulated in separate unit dosage forms in a mannersimilar to that described above.

Fixed combinations of ACE inhibitor and drug that acts at serotoninreceptors are more convenient and are preferred, especially in tablet orcapsule form for oral administration.

In formulating the compositions, the active substances, in the amountsdescribed above, are compounded according to accepted pharmaceuticalpractice with a physiologically acceptable vehicle, carrier, excipient,binder, preservative, stabilizer, flavor, etc., in the particular typeof unit dosage form.

Illustrative of the adjuvants which may be incorporated in tablets arethe following: a binder such as gum tragacanth, acacia, corn starch orgelatin; an excipient such as dicalcium phosphate or cellulose; adisintegrating agent such as corn starch, potato starch, alginic acid orthe like; a lubricant such as stearic acid or magnesium stearate; asweetening agent such as sucrose, lactose or saccharin; a flavoringagent such as orange, peppermint, oil of wintergreen or cherry. When thedosage unit form is a capsule, it may contain in addition to materialsof the above type a liquid carrier such as a fatty oil. Various othermaterials may be present as coatings or to otherwise modify the physicalform of the dosage unit. For instance, tablets or capsules may be coatedwith shellac, sugar or both. A syrup of elixir may contain the activecompound, water, alcohol or the like as the carrier, glycerol assolubilizer, sucrose as sweetening agent, methyl and propyl parabens aspreservatives, a dye and a flavoring such as cherry or orange.

Many of the active substances described above form commonly known,pharmaceutically acceptable salts such as alkali metal and other commonbasic salts or acid addition salts, etc. References to the basesubstances are therefore intended to include those common salts known tobe substantially equivalent to the parent compound

The formulations as described above will be administered for a prolongedperiod, that is, for as long as inhibition of loss of cognitive functionis to continue.

Sustained release forms of such formulations which may provide suchamounts biweekly, weekly, monthly and the like may also be employed. Adosing period of at least one to two weeks are required to achieveminimal benefit.

BRIEF DESCRIPTION OF FIGURES

The accompanying Figure is a series of graphs or charts of test dataobtained as described in the working Example 7 which shows influence ofSQ29,852 (1.0 ng/kg i.p. b.d.) and the 5-HT₃ receptor antagonist,zacopride (10 ng/kg i.p. b.d.) administered alone or in combination onthe latency of young adult mice to move from the white to blackcompartment of the white and black test box. Mean±S.E.M., n=5. *P<0.001,significant difference compared with control group (Student's test).

The following Examples represent preferred embodiments of the presentinvention.

EXAMPLE 1

An injectable solution for use in inhibiting loss of cognitive functionis produced as follows:

    ______________________________________                                        Ceranapril (SQ29,852)   500 mg                                                Methyl paraben           5 mg                                                 Propyl paraben           1 mg                                                 Sodium chloride          25 g                                                 Water for injection qs.  5 l.                                                 ______________________________________                                    

The SQ29,852, preservatives and sodium chloride are dissolved in 3liters of water for injection and then the volume is brought up to 5liters. The solution is filtered through a sterile filter andaseptically filled into presterilized vials which are then closed withpresterilized rubber closures. Each vial contains 5 mL of solution in aconcentration of 0.5 mg of active ingredient per mL of solution forinjection.

A zacopride injectable solution for use in combination with ceranaprilfor treating or inhibiting loss of cognitive function is prepared asdescribed above except 100 mg zacopride is employed in place ofceranapril.

The so-prepared injectable solutions may be administered separately oras a single injection to inhibit loss of cognitive function.

EXAMPLE 2

Two piece #1 gelatin capsules each containing 100 mg of ceranapril arefilled with a mixture of the following ingredients:

    ______________________________________                                        Ceranapril             100 mg                                                 Zacopride               1 mg                                                  Magnesium stearate      7 mg                                                  USP lactose            193 mg.                                                ______________________________________                                    

The resulting capsules are useful in inhibiting loss of cognitivefunction.

EXAMPLE 3

A captopril formulation suitable for oral administration for use incombination with a 5-HT₃ antagonist in inhibiting loss of cognitivefunction is set out below.

1000 tablets each containing 100 mg of1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline were produced from thefollowing ingredients.

    ______________________________________                                        1-[(2S)-3-Mercapto-2-methylpropionyl]-                                                                  100    g                                            L-proline (captopril)                                                         Corn starch               50     g                                            Gelatin                   7.5    g                                            Avicel (microcrystalline cellulose)                                                                     25     g                                            Magnesium stearate        2.5    g                                            ______________________________________                                    

The captopril and corn starch are admixed with an aqueous solution ofthe gelatin. The mixture is dried and ground to a fine powder. TheAvicel and then the magnesium stearate are admixed with the granulation.This is then compressed in a tablet to form 1000 tablets each containing0.5 mg of active ingredient which together with the drug that acts atserotonin receptors ICS 250930 (5-HT₃ antagonist) is used for inhibitingloss of cognitive function.

The ICS 250930 (3α-tropanyl-1H-indole-3-carboxylic acid ester) isformulated as 100 mg tablets as described above with respect tocaptopril.

The captopril tablets and ICS 250930 tablets may be administered toinhibit loss of cognitive. function.

EXAMPLE 4

By substituting 100 g of 1-(3-mercapto-2-D-methylpropanoyl)-L-prolinefor the captopril in Example 3 and adding 100 mg Granisetron, 1000tablets each containing 100 mg of the1-(3-mercapto-2-D-methylpropanoyl)-L-proline and 1 mg Granisetron areproduced which are useful in inhibiting loss of cognitive function.

EXAMPLE 5

1000 tablets each containing 50 mg of fosinopril and 0.5 mg MDL 72222(1αH,3α,5αH,tropan-3-yl-3,5-dichlorobenzoate) are produced from thefollowing ingredients:

    ______________________________________                                        Fosinopril             50     g                                               MDL 72222              0.5    g                                               Lactose                100    g                                               Avicel                 150    g                                               Corn starch            50     g                                               Magnesium stearate     5      g                                               ______________________________________                                    

The fosinopril, MDL 72222, lactose and Avicel are admixed, then blendedwith the corn starch. Magnesium stearate is added. The dry mixture iscompressed in a tablet press to form 1000 505 mg tablets each containing50.5 mg of active ingredients. The tablets are coated with a solution ofMethocel E 15 (methyl cellulose) including as a color a lake containingyellow #6. The resulting tablets are useful in inhibiting loss ofcognitive function.

EXAMPLE 6

Two piece #1 gelatin capsules each containing 100 mg of enalapril and100 mg zacopride are filled with a mixture of the following ingredients:

    ______________________________________                                        Enalapril             100    mg                                               Zacopride             0.1    mg                                               Magnesium stearate    7      mg                                               USP lactose           193    mg.                                              ______________________________________                                    

The resulting capsules are useful in inhibiting loss of cognitivefunction.

EXAMPLE 7

A combination of ceranapril (SQ29,852, ACE inhibitor) and zacopride(5-HT₃ antagonist) as well as ceranapril alone and zacopride alone, weretested in a single mouse habituation test (Costall et al, supra) fortheir ability to improve basal cognitive performance.

Methods

The studies used male albino (BKW) mice weighing 25-30 g. In their homeroom mice were housed in groups of 10 and were given free access to foodand water. The mice were kept on a 12 hour light and 12 hour dark cyclewith lights off at 08.00 a.m. and on at 08.00 p.m.

The test apparatus consisted of an open-topped box (45×27×27 cm)two-fifths painted black and illuminated under a dim red light (1×60 W)and partitioned from the remainder of the box which was brightlyilluminated with a 100 W light source located 17 cm above the box.Access between these two areas was enabled by means of a 7.5×7.5 cmopening located at floor level in the centre of the partition (whichalso served to prevent diffusion of light between the two compartmentsof the test box). The floor area was lined into 9 cm squares.

The habituation test was carried out daily by placing the same mice eachday in the centre of the white section of the test box (mice taken fromdark home environment in a dark container to the experimental roommaintained in low red lighting, and would normally be averse to thebright white conditions). Testing was carried out between 8.30 a.m. and12.30 p.m. The test period was 5 minutes per day. Behaviour was assessedvia remote video recording, and the following measures taken:

Latency of initial movement from the white to the black section (sec).

Generally, as mice habituated to the test system they would move intothe black section of the box where behavioural exploration was exhibitedas exploratory rears and line crossings. Habituation occurred over a 5day period, after which time animals moved almost immediately into theblack where they exhibited most behavior.

Results

Mice exposed repeatedly to the environment of a black:white box in whichthe brightly-lit white section is aversive `learn` over a period of 4-5days to avoid the aversive environment. They therefore move more rapidlyfrom the white to the black environment and spend a greater proportionof test time in the black section.

The habituation process, in which animals `learn` to avoid thebright-lit compartment and spend more time in the black, is seen as aprogressive increase in % time spent in black.

When SQ29,852 (1.0 ng/kg i.p. b.d.) was administered in combination witha sub-threshold cognitive enhancing dose of a 5-HT₃ receptor antagonist,benzamide zacopride (10.0 ng/kg i.p. b.d.), synergism (over SQ29,852alone and zacopride alone) was observed by a significant increase in thebasal performance of the mice (noted by a reduction in the latency ofanimals to move from the white to black compartment accompanyingFigure).

Discussion

The present studies demonstrate that the combination of SQ29,852 with asub-threshold cognitive enhancing dose of zacopride (5-HT₃ receptorantagonist) induced a synergistic effect noted by a marked improvementin the basal performance of the mice.

The above test results clearly show that the combination of an ACEinhibitor and a drug that acts at serotonin receptors is useful ininhibiting loss of cognitive function.

What is claimed is:
 1. A method for inhibiting loss of cognitivefunction not associated with Alzheimer's disease, in a mammalian specie,which comprises administering to a mammalian specie in need of suchtreatment a therapeutically effective amount of a combination of anangiotensin converting enzyme (ACE) inhibitor with a drug that acts atserotonin receptors, wherein the ACE inhibitor is employed in a weightratio to the drug that acts at aserotonin receptors of within the rangeof from about 0.0005:1 to about 1×10⁷ :1; and wherein the drug that actsat serotonin receptors is zacopride; 3α-tropanyl-1H-indole-3-carboxylicacid ester;[endo]N-(9-methyl-9-azabicyclo-[3,3,1]-non-3-yl)-1-methyl-1H-indazole-3-carboxamide;1αH,3α,5αH-tropan-3-yl-3,5-dichlorobenzoate; ondansetron; buspirone orritanserin.
 2. The method as defined in claim 1 wherein the angiotensinconverting enzyme inhibitor is a phosphonate substituted amino or iminoacid or salt thereof, a proline derivative, a substituted prolinederivative, a carboxyalkyl dipeptide derivative, a phosphinylalkanoylproline derivative or a phosphonamidate derivative.
 3. The method asdefined in claim 1 wherein said angiotensin converting enzyme inhibitoris a proline derivative or a substituted proline derivative.
 4. Themethod as defined in claim 1 wherein said angiotensin converting enzymeinhibitor is a carboxyalkyl dipeptide derivative.
 5. The method asdefined in claim 1 wherein said angiotensin converting enzyme inhibitoris a phosphinylalkanoyl proline derivative, a phosphoramidatederivative, or a phosphonate substituted amino or imino acid or saltthereof.
 6. The method as defined in claim 1 wherein said angiotensinconverting enzyme inhibitor is captopril.
 7. The method as defined inclaim 1 wherein said angiotensin converting enzyme inhibitor isenalapril or lisinopril.
 8. The method as defined in claim 1 whereinsaid angiotensin converting enzyme inhibitor is zofenopril orfosinopril.
 9. The method as defined in claim 1 wherein said angiotensinconverting enzyme inhibitor is(S)-1-[6-amino-2-[[hydroxy(4-phenylbutyl)phosphinyl]-oxy]-1-oxohexyl]-L-proline(ceranapril).
 10. The method as defined in claim 1 wherein the drug thatacts at serotonin receptors is zacopride or buspirone.
 11. The method asdefined in claim 1 wherein the drug that acts at serotonin receptors iszacopride.
 12. The method as defined in claim 1 wherein the ACEinhibitor is ceranapril and the drug that acts at serotonin receptors iszacopride.
 13. The method as defined in claim 1 wherein said angiotensinconverting enzyme inhibitor is administered in single or divided dosesof from about 0.1 to about 500 mg/one to four times daily and the drugthat acts at serotonin receptors is administered in single or divideddoses of from about 1 μg to about 200 mg/1 to 4 times daily.
 14. Themethod as defined in claim 1 wherein the angiotensin converting enzymeinhibitor is employed in a weight ratio to the drug that acts atserotonin receptors of within the range of from about 0.002:1 to about25×10⁴ :1.
 15. A pharmaceutical combination comprising an angiotensinconverting enzyme inhibitor and a drug that acts at serotonin receptorswherein the ACE inhibitor is employed in a weight ratio to the drug thatacts at serotonin receptors of within the range of from about 0.0005:1to about 1×10⁷ :1; and wherein the drug that acts at serotonin receptorsis zacopride; 3α-tropanyl-1H-indole-3-carboxylic acid ester;N-(9-methyl-9-azabicyclo-non-3-yl)-1-methyl-1H-indazole-3-carboxamide;1αH,3α,5αH-tropan-3-yl-3,5-dichlorobenzoate; ondansetron; buspirone orritanserin.
 16. The combination as defined in claim 15 wherein theangiotensin converting enzyme inhibitor is a phosphonate substitutedamino or imino acid or salt thereof, a proline derivative, a substitutedprolin derivative, a carboxalkyl dipeptide derivative, aphosphinylalkanoyl proline derivative or a phosphonamidate derivative.17. The combination as defined in claim 15 wherein said angiotensinconverting enzyme inhibitor is a proline derivative or a substitutedproline derivative.
 18. The combination as defined in claim 15 whereinsaid angiotensin converting enzyme inhibitor is a carboxyalkyl dipeptidederivative.
 19. The combination as defined in claim 15 wherein saidangiotensin converting enzyme inhibitor is a phosphinylalkanoyl prolinederivative, a phosphoramidate derivative, or a phosphonate substitutedamino or imino acid or salt thereof.
 20. The combination as defined inclaim 15 wherein said angiotensin converting enzyme inhibitor iscaptopril, enalapril, fosinopril, zofenopril, lisinopril or ceranapril.21. The combination as defined in claim 17 wherein the drug that acts atserotonin receptors is zacopride or buspirone.
 22. The combination asdefined in claim 15 wherein the angiotensin converting enzyme inhibitoris ceranapril and the drug that acts at serotonin receptors iszacopride.